Primary cilia are typically solitary, immotile cellular appendages that project from nearly all mammalian cell types. They provide important sensory and signaling functions and defects in the formation or function of primary cilia leads to a class of human diseases called ciliopathies. Due to the ubiquity of primary cilia, ciliopathies are associated with a wide range of clinical features, including cystic kidney disease, retinal degeneration, obesity, skeletal defects, hypogonadism, anosmia, behavioral disturbances, social deficits and intellectual disability. The range of neurological disorders associated with ciliopathies indicates that cilia play important roles in the brain. In fact, most neurons throughot the mammalian brain possess a primary cilium that is enriched for specific G protein-coupled receptors (GPCRs), such as dopamine receptor 1 (D1). It is thought that neuronal cilia sense neuromodulators and provide specialized signaling. Yet, the roles of primary cilia in neuronal function remain largely unknown. We have discovered that trafficking of GPCRs to and from neuronal cilia is dynamic and regulation of GPCR ciliary localization is disrupted in mouse models of the human ciliopathy Bardet-Biedl syndrome (BBS). For example, D1 shows abnormal accumulation in cilia on striatal and amygdala neurons in BBS mice. Interestingly, these mice display reduced locomotor activity and adult onset obesity; phenotypes that are consistent with defective D1 signaling. We hypothesize that trafficking of GPCRs into and out of cilia coordinates receptor signaling and disruption of ciliary localization alters the regulation o GPCR signaling. The objectives of this application are to determine the effects of D1 ciliary accumulation and loss of D1 ciliary localization on D1 expression, trafficking and signaling. The outcomes of this work are expected to fundamentally advance our understanding of the role of cilia in the regulation of D1 signaling. These studies will provide the critical insights into ciliry signaling that are needed to establish the importance of GPCR localization in neuronal cilia throughout the brain.